# Defining the molecular determinants of mesenchymal lineage allocation in lung development and disease

> **NIH NIH R00** · CHILDREN'S HOSP OF PHILADELPHIA · 2021 · $249,000

## Abstract

PROJECT ABSTRACT
The lung is an architecturally complex organ, comprised of specialized epithelial cells surrounded by a dense
network of mesenchyme. Recent work from our lab as well as others has shown that spatially discreet
epithelial to mesenchymal niche signaling is required for proper lung development as well as adult tissue
quiescence and regeneration. These studies prompted us to develop an in vivo pathway reporter system to
monitor mesenchymal signaling pathway activity. Using this reporter system, we have deconstructed the
mesenchyme and classified lineages using innovative methods; Single-Cell and Lineage-Seq transcriptome
profiling, three-dimensional spatial orientation, in vivo response to injury and ex vivo niche support capacity.
We have characterized a mesenchymal alveolar niche cell (MANC) as Wnt responsive, expresses platelet-
derived growth factor receptor alpha (PDGFRa), and is critical for alveolar epithelial cell growth and self-
renewal. In contrast, the Axin2+ myofibrogenic progenitor (AMP) cell generates pathologically deleterious
myofibroblasts after injury. These studies provide a platform for defining the cellular and molecular framework
of the lung mesenchymal niches. Moving forward, in Aim 1 of this proposal, I will examine the lineage ontogeny
of Axin2-positive mesenchyme and elucidate the role of PDGFRa-signaling in controlling lineage allocation and
development of the alveolar niche during the postnatal period of alveologenesis. In the independent phase
outlined in Aim 2, I will define mechanisms controlling the pro-regenerative versus myofibrogenic responses in
the mesenchyme after acute lung injury. Based on bioinformatic analyses using multicellular alignment of
ligand and cognate receptor pairs from the alveolar niche, I will define the impact of Notch and Cxcr4 pathways
in provoking the myofibrogenic response from the AMP lineage, in vivo. Importantly, this proposal outlines a
rigorous training plan that will establish the foundation to advance my career in biomedical research.

## Key facts

- **NIH application ID:** 10247829
- **Project number:** 5R00HL141684-04
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** Jarod Zepp
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $249,000
- **Award type:** 5
- **Project period:** 2020-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10247829

## Citation

> US National Institutes of Health, RePORTER application 10247829, Defining the molecular determinants of mesenchymal lineage allocation in lung development and disease (5R00HL141684-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10247829. Licensed CC0.

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